The development of Type I diabetes has been linked to the T cell compartment in the two rodent models, and to the MHC region in both rodents and man. This proposal will examine the hypothesis that these two phenomena arise from the dependence of normal thymic selection processes on the expressed products of the MHC region, specifically that this selective interaction between T cell precursors and MHC-bearing stromal elements in the thymus of the NOD mouse results in the development of an abnormal repertoire of T cells which is capable of initiating the pancreatic beta-cell-specific damage leading to insulin deficiency. The level at which the T cell repertoire is distorted will be determined by evaluating the clonal alloreactivity patterns of cells at various levels of T cell development which have been generated in the context of the NOD major histocompatibility complex (MHC), using hybridomas generated from T cells expressing a unique T cell receptor V beta region defined by the monoclonal antibody KJ23. This V beta region has the apparently unique characteristic of forming receptor heterodimers recognizing a limited array of allo-MHC antigens which vary in relation to the selecting MHC regions, particularly the Class II regions. The surface expression of the NOD MHC Class II molecule will also be assessed by flowcytometric and immunoprecipitation analyses in the attempt to detect regulatory defects which might underly its generation of the abnormal T cell compartment in the NOD.